tbuckley/cabot-search huggingface dataset:
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 29-month (mo) follow-up from CheckMate 648.
Authors: Ken Kato, Jaffer A. Ajani, Yuichiro Doki, Jianming Xu, Lucjan Wyrwicz, Satoru Motoyama, Takashi Ogata, Hisato Kawakami, Chih-Hung Hsu, Antoine Adenis, Farid El Hajbi, Maria Di Bartolomeo, Maria Ignez Freitas Melro Braghiroli, Eva Holtved, Mariela A. Blum Murphy, Apurva Patel, Nan Hu, Yasuhiro Matsumura, Ian Chau, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2023)

290 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]
The role of gene expression of CDC37 in colorectal cancer (CRC).
Authors: Hiroyuki Arai, Yasmine Baca, Francesca Battaglin, Sandy Algaze, Priya Jayachandran, Shivani Soni, Zhang Wu, Jae Ho Lo, Davendra P.S. Sohal, Richard M. Goldberg, Michael J. Hall, Aaron James Scott, Jimmy J. Hwang, Emil Lou, Benjamin Adam Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2023)

237 Background: CDC37-HSP90 axis is an essential chaperoning system for stabilization of kinases. CDC37 determines selectivity of client kinases recognized by HSP90. We previously showed patients with CDC37-dependent ( CDC37 high expression) colorectal cancer (CRC) derived more benefit from regorafenib and bevacizumab both of which target HSP90 client kinases or signaling pathway, but not from cetuximab which targets HSP90 non-client kinase. However, molecular characteristics and interaction with relevant signaling pathways in CDC37-dependent CRC are largely unknown. Methods: We retrospectively reviewed CRC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix AZ). Next-generation sequencing of DNA and RNA (whole-transcriptome sequencing) and immunohistochemistry were performed. Molecular profiles between top quartile transcripts per million for CDC37 expression (Q4, CDC37-high: n = 5056) and bottom quartile (Q1, CDC37-low: n = 5056) were compared for gene mutations, microsatellite instability (MSI) status, PD-L1 expression, co-expression of HSP90 genes ( HSP90AA1 and HSP90AB1), MAPK pathway activity score (MPAS), T-cell inflamed signature, and cell infiltration in the tumor microenvironment (TME) assessed by QuantiSEQ. Gene set enrichment analysis (GSEA) was performed between CDC37-high (Q4) and CDC37-low (Q1) tumors. Results: KRAS mutations trended higher in CDC37-high tumors compared to CDC37-low tumors (49.5% vs 47.1%) while APC (76.9% vs 72.3%), TP53 (75.5% vs 71.8%) and TCF7L2 (5.0% vs 3.5%) mutations were significantly higher in CDC37-high tumors compared to CDC37-low tumors (q &lt; 0.05). No significance in expression quartiles were observed for dMMR/MSI-H or PD-L1 expression. HSP90AA1 and HSP90AB1 expression levels were significantly higher in CDC37-high tumors (2.9-fold and 2.6-fold in median, respectively; both q&lt; 0.05). Both MPAS and T-cell inflamed signatures were significantly higher in CDC37-high tumors ( q&lt; 0.05). Infiltration of NK cells, Tregs, neutrophils, M1 macrophages, and B-cells were greater in CDC37-high tumors (q &lt; 0.05). GSEA showed several signaling pathways, such as KRAS, TGF-beta, hypoxia, WNT-beta catenin, and PI3K-AKT-MTOR, were enriched in CDC37-high tumors. Conclusions: Highly CDC37-expressed (CDC37-dependent) CRC was associated with aberrant TME where abundance of immune cell infiltrate and broad activation of kinase-related signaling pathways were evident. Our results support the kinase-stabilizing function of CDC37 in CRC. Further investigations combined with survival data are warranted to address the prognostic and predictive values of CDC37 expression in targeted therapies of CRC.
Clinical significance of CA125 in unresectable pancreatic cancer treated with first-line chemotherapy.
Authors: Iori Motoo, Takayuki Ando, Satoshi Yuki, Ken Ito, Akira Ueda, Yosuke Kito, Miho Sakumura, Shinya Kajiura, Jun Matsuno, Yoshifumi Nakamura, Yuma Inoue, Nobuhiko Hayashi, Ayumu Hosokawa, Kazuto Shibuya, Haruyoshi Tanaka, Mina Fukasawa, Tsutomu Fujii, Ichiro Yasuda
Journal: Journal of Clinical Oncology (2023)

745 Background: Serum CA125 is a potential biomarker for diagnosis of peritoneal metastasis in gastric cancer. However, its significance of pancreatic cancer (PC) has not been investigated. Therefore, we aimed to clarify association between serum CA125 and ascites burden, and its kinetics during first-line chemotherapy for PC. Methods: This multicenter retrospective study comprised PC patients who received FOLFIRINOX or gemcitabine plus nab-paclitaxel in first-line setting between Jan 2014 and Dec 2021. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before chemotherapy. The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and clinical response during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 109 patients from 3 hospitals were assessable. The overall survival (OS) was significantly shorter in elevated group than that in non-elevated group (median, 10.7 vs. 21.3 months, p = 0.0002). The median value of CA125 before chemotherapy was elevated according to ascites burden (Non, 36U/ml; mild, 173U/ml; moderate/severe, 575U/ml; p &lt; 0.0001). CA125 elevation, CA19-9 elevation, poor performance status and poor glasgow prognostic score were independent prognostic factors in multivariate analysis. After chemotherapy, the median first-time measure of CA125 was performed in day 41. Among patients with peritoneal dissemination, the median change of CA125 was correlated with clinical response (CR/PR, -0.55%/day; SD, -0.24%/day; PD, 3.35%/day, p = 0.004). After chemotherapy, first-time measure of CA125 was performed in a median of day 41. According to the ROC curve analysis, the optimal cut-off value of increase in CA125 for progressive disease was 1.56 %/day (specificity 94.1%, sensitivity 80%). The median PFS and OS were 1.4 and 6.6 months in increased group and 3.3 months and 14.0 months in non-increased group, respectively (p = 0.016 and p = 0.028). Conclusions: CA125 is considered a clinically useful marker in unresectable PC treated with first-line chemotherapy because CA125 above the ULN is a poor prognostic factor for OS and an increased CA125 can be an early predictor of progression in patients with peritoneal dissemination.
Prognostic value of tumor budding in patients with stage II and III colon cancer: A single-institution experience.
Authors: David Viñal, Antonio Rueda-Lara, Daniel Martinez-Perez, Patricia Zwisler, Andrea Garcia-Leal, Iciar Ruiz-Gutierrez, Diego Jiménez-Bou, Jesus Peña-Lopez, Maria Alameda-Guijarro, Gema Martin-Montalvo, Pablo Perez-Wert, Sergio Martínez-Recio, Maria Elena Palacios, Ismael Ghanem, Ana B. Custodio, Laura Gutiérrez-Sainz, Jaime Feliu, Nuria Rodriguez Salas
Journal: Journal of Clinical Oncology (2023)

247 Background: Tumor budding has recently been recognized as one important prognostic factor for recurrence in patients with localized colon cancer. Nevertheless, not all guidelines consider tumor budding in the decision-making process for selecting patients for adjuvant chemotherapy. We aim to assess the prognostic value of tumor budding in a cohort of patients with stage II and III colon cancer. Methods: We included patients with pathologically confirmed diagnosis of stage II and III colon cancer at Hospital Universitario La Paz and tumor budding assessment available, from October 2016 to August 2021. Tumor budding was reported following the recommendations from the 2016 International Tumour Budding Consensus Conference. Results: A total of 390 patients were included. Patients were predominantly men (55%) and had a median age of 75 (35-95). Fifty percent of the patients were stage II and 50% were localized in the right colon. Tumor budding was reported as low, intermediate, and high in 186 (48%), 110 (28%), and 94 (24%) patients, respectively. After a median follow up of 18 months, 63 recurrences and 73 deaths were observed. Time to recurrence was significantly worse for patients with high tumor budding. At 24 months, 91%, 79%, and 67% of patients with low, intermediate and high budding were recurrence-free. Median TTR was not reached in any of the three cohort (P &lt;0.001). Comparing high vs low or intermediate budding, the hazard ratio (HR) for recurrence was 0.13 [confidence interval (CI)95%: 0.05 to 0.32; P &lt; 0.001]. We performed a univariate analysis with the most relevant clinic-pathological features. T4, N2, R1, bowel obstruction or perforation, positive resection margins (R1), lymphovascular or perineural invasion, and mismatch repair protein status were found to be statistically associated with TTR and entered the multivariate analysis. T4, N2, R1 and high tumor budding (HR: 0.48 [CI95%: 0.28 to 0.84], P = 0.011) were independent prognostic factors for recurrence at the multivariate analysis. Conclusions: High tumor budding is an adverse independent prognostic factor for recurrence in patients with stage II and III colon cancer and should be acknowledge when considering adjuvant chemotherapy.
A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of Neo<i>RAS</i> wild-type metastatic colorectal cancer.
Authors: Yuri Yoshinami, Hiroki Osumi, Atsuo Takashima, Ryoichi Sawada, Kota Ouchi, Takeru Wakatsuki, Akira Ooki, Izuma Nakayama, Shota Fukuoka, Mariko Ogura, Daisuke Takahari, Keisho Chin, Hidekazu Hirano, Hirokazu Shoji, Natsuko Okita Okita, Narikazu Boku, Ken Kato, Naoki Ishizuka, Kensei Yamaguchi, Eiji Shinozaki
Journal: Journal of Clinical Oncology (2023)

206 Background: The ’’Neo RAS’’ phenomenon, in which tissue rat sarcoma viral oncogene homolog ( RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because epidermal growth factor receptor (EGFR) inhibitors, which were originally considered to be ineffective, may converted to be effective. This multi-center study investigated its incidence and clinicopathological characteristics that are still unclear. Methods: 107 mCRC patients with tissue RAS MT, confirmed using MEBGEN RASKET-B, who were refractory or intolerant to previous chemotherapies, including fluoropyrimidines, oxaliplatin, or irinotecan were enrolled in 4 institutions from June 2021 to August 2022. The RAS status in ctDNA was investigated after prior chemotherapy using ONCOBEAM TM RAC CRC. Clinicopathological characteristics were compared between patients with RAS MT and RAS WT (Neo RAS) in ctDNA. Results: The incidence of Neo RAS WT mCRC was 21.5% (23/107). The frequency of Neo RAS in KRAS exon 2 was significantly lower than that in other alleles such as exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). There were significant differences in frequency of Neo RAS between male vs female (30.6% [19/62] vs 8.9% [4/45], P = 0.008), absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P &lt; 0.001), and between two groups divided at the median: tumor diameter (&gt; 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P &lt; 0.001), carcinoembryonic antigen level (&gt; 38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), carbohydrate antigen 19-9 level (&gt; 158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). Logistic regression multivariate analysis, absence of liver metastasis (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012) and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the appearance of Neo RAS WT mCRC. Conclusions: Original RAS status in tissue, tumor diameter and liver metastasis are related to conversion to Neo RAS WT mCRC.
Molecular genetic sequencing of neuroendocrine tumors of the gastrointestinal tract.
Authors: Alexandra Androsova, Rashida Orlova, Marat Gordiev, Anastasia Ivanova, Natalia P. Belyak, Svetlana Kutukova
Journal: Journal of Clinical Oncology (2023)

651 Background: The objective of this work was to evaluate the molecular and genetic features of the NET gastrointestinal tract. Genomic sequencing of 30 tumor samples of the latest generation was carried out and the data obtained were evaluated. Methods: In total, 30 tumor blocks of patients with gastrointestinal NET were tested by the new generation sequencing (NGS) method. The following genes were analyzed: ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDK12, CHEK1, CHEK2, EPCAM, FANCL, MLH1, MSH2, NBN, NF1, PALB2, PMS2, RAD51B, RAD51C, RAD51D, RAD54L, STK11, TP53, POLE, KRAS, NRAS, BRAF, EGFR, ERBB2, PIK3CA, MET ex14, BAT25, BAT26, NR21, NR24, MONO27, KIT, PDGFRA, Pi3Ca. Preparation of libraries for sequencing was carried out using NimblGen SepCapEZ Choice. Sequencing was performed on the Illumina MiSeq device. Results: In the study cohort of patients whose tumor blocks were sent for examination by the NGS method, there were more women – 19 (63.3%) than men – 11 (36.7%). When analyzing the age of patients, it should be noted that among all age groups, elderly patients predominated (60-74 years according to the WHO classification, 2016) – 12 (40%). In the majority of patients – 10 (33.3%) – the primary tumor focus was localized in the pancreas, in 6 (20%) patients it was primarily affected stomach, 7 (23.3%) – small intestine. Other parts of the gastrointestinal tract were affected much less frequently: the colon – in 1 (3.3%) patients. According to the division according to the degree of differentiation of gastrointestinal NET10 tumors had a degree of differentiation G1 (33.3%), 16 -G3 (54.3%), 4– G3 (13.3%). In the tumor sample of a patient with gastric NET G1 (Ki 67 = 2%), POLE mutations were found: c.2276G &gt; A, p.R759H and CHEK2: c.470T &gt; C, p.I157T. Also, mutations MLH1: c.199G &gt; A, p.G67R BRCA1: c.1881 were found in the tumor sample of another patient with gastric NET G2 (Ki 67 = 7%). Conclusions: To improve the survival rates of patients, it is worth paying special attention to the molecular genetic study of the NET gastrointestinal tract. It is molecular genetic profiling that can become the basis for building more individualized algorithms for treating patients. The results of this study allow us to count on the fact that when conducting a study on a larger cohort of patients with gastrointestinal NET, it is possible to obtain results that will expand our knowledge of this nosology and allow us to supplement the already available information about prognosis factors and predictors of response to treatment.
Impact of <i>RAS </i>and<i> BRAF </i>heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.
Authors: Takeshi Yamada, Nobuhisa Matsuhashi, Takao Takahashi, Keiji Hirata, Takeshi Nagasaka, Yuki Nakamura, Kazuhiro Sakamoto, Keiji Koda, Kazuhiro Hiramatsu, Hiroshi Matsuoka, Hidekazu Kuramochi, Hideyuki Ishida, Kozo Kataoka, Hajime Yokomizo, Yoshinori Kagawa, Mitsukuni Suenaga, Ryo Ohta, Akihisa Matsuda, Hiroshi Yoshida
Journal: Journal of Clinical Oncology (2023)

219 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS nor BRAF mutations in their primary tumors have them in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect these mutations in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS nor BRAF mutations in their primary tumors, but who had them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS nor BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy, and at the time they acquired resistance. We detected RAS, BRAF (V600E), and PIK3CA mutations using digital polymerase chain reaction. Results: In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 10, 4, and 2 of the 100 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Of those, 3 experienced a complete response (CR), 72 had a partial response (PR), 12 had stable disease (SD), and 2 had progressive disease (PD). Of 14 patients who had measurable tumors and RAS or BRAF mutations in the ctDNA, 11 (79%) had a PR and 3 (21%) had SD. Of 75 patients who had measurable tumors and no RAS or BRAF mutations in the ctDNA, 3 (4%) experienced a CR, 61 (81%) had PR, 9 (12%) had SD, and 2 (3%) had PD. Patients with RAS or BRAF mutations and patients with neither mutation had response rates of 79% and 85%, respectively. There was no significant difference. Conclusions: As we previously reported, incidence of RAS and BRAF heterogeneity were 10% and 4%, respectively. Heterogeneity of RAS and BRAF mutations had no effect on the response rate of EGFR blockade as first line chemotherapy. Other possible causes of resistance could be MET or HER-2 amplification, PIK3CA mutation, or ALK fusion. The effect of heterogeneity on the duration of response is of great interest; however, one-third of patients are still undergoing treatment with EGFR blockade. Clinical trial information: 000031177 .
Dosimetric comparison of target volume coverage and sparing of organs at risk (OARs) between helical intensity modulated radiotherapy (H-IMRT) versus volumetric arc therapy (VMAT) for mid and lower thoracic oesophageal carcinoma.
Authors: Vatsala Yagnik, Samir Batham, Kinjal Jani, Maitri Gandhi, Vega Jain, Ruchi Rajgor, Jagdish Kothari, Devendra Parikh, Viraj Kiran Lavingia, Bharat Prajapati
Journal: Journal of Clinical Oncology (2023)

469 Background: To evaluate the effectiveness of H-IMRT and VMAT in covering target volume while adequately sparing the OARs for patients with mid and distal oesophageal carcinoma, on the basis of dosimetric analysis. Methods: The target areas and organs at risk in 30 patients with locally advanced carcinoma oesophagus undergoing neo-adjuvant chemo-radiotherapy were specified and transmitted to Eclipse, Version 13.6, Varian Medical Systems) &amp; Accuray Treatment Planning System (Accuray Precision, Version 2.1.4, Accuray Medical System). Two plans (H-IMRT and VMAT) were generated for each patient for a total dose of 41.4 Gy delivered to the PTV in 23 fractions, and the Homogeneity Index (HI), Conformity Index (CI) and the dose distribution to the OARs (spinal cord, heart, lungs, kidneys and liver) were compared using dose volume histograms. Results: H-IMRT resulted in a more homogeneous dose distribution to the target (HI- 0.059) as compared to VMAT (HI- 0.07) [p-0.004]. The Conformity Indices showed no significant difference between the two techniques (H-IMRT – 0.989, VMAT – 0.987) [p-0.66]. VMAT resulted in a significantly less dose to the spinal cord (23.598 Gy vs .25.657 Gy) [p-0.021]. With VMAT plans, the heart mean dose (18.101 Gy vs. 20.031) [p- 0.00007], heart V40 (4.902% vs. 6.143) [p-0.002,] the averaged lung V20 [p-0.00005] and the mean dose to the left kidney (3.84 Gy vs. 4.721 Gy) [p- 0.010] were significantly less as compared to H-IMRT No statistically significant difference in both techniques with respect to heart V30, Mean Lung Dose (MLD), and mean dose to the righ and left kidney was observed Conclusions: VMAT proved to be better at sparing of OARs whilst providing almost the same Conformity as compared to a H-IMRT. H-IMRT has statistically better dose homogeneity but, it tends to deposit a slightly higher dose to the OARs. Whether the aforementioned differences in the dosimetric parameters translate into clinical benefits has to be evaluated by clinical outcome studies.